Papillomaviruses are non-enveloped DNA viruses that induce hyperproliferative lesions of the epithelia. The papillomaviruses are widespread in nature and have been identified in higher vertebrates. Viruses have been characterized, amongst others, from humans, cattle, rabbits, horses, and dogs. The first papillomavirus was described in 1933 as cottontail rabbit papillomavirus (CRPV). Since then, the cottontail rabbit as well as bovine papillomavirus type 1 (BPV-1) have served as experimental prototypes for studies on papillomaviruses. Most animal papillomaviruses are associated with purely epithelial proliferative lesions, and most lesions in animals are cutaneous. In the human, there are more than 75 types of papillomavirus that have been identified and they have been catalogued by site of infection: cutaneous epithelium and mucosal epithelium (oral and genital mucosa). The cutaneous-related diseases include flat warts, plantar warts, etc. The mucosal-related diseases include laryngeal papillomas and anogenital diseases such as cervical carcinomas.
There are more than 25 HPV types that are implicated in anogenital diseases, these are grouped into “low risk” and “high risk” types. The low risk types include HPV type 6 and type 11, and induce mostly benign lesions such as condyloma acuminata (genital warts) and low grade squamous intraepithelial lesions (SIL). In the United States, 1% of the sexually active population has genital warts of which 90% is attributed to HPV-6 and HPV-11.
The high risk types are associated with high grade SIL, cervical and anal cancers and include most frequently HPV types 16, 18, 31, 33, 35, 45, 52, and 58. The progression from low-grade SIL to high-grade SIL is much more frequent for lesions that contain high risk HPV-16 and 18 as compared to those that contain low risk HPV types. In addition, only four HPV types are detected frequently in cervical cancer (types 16, 18, 31 and 45). About 500,000 new cases of invasive cancer of the cervix are diagnosed annually worldwide.
Treatments for genital warts include physical removal such as cryotherapy, CO2 laser, electrosurgery, or surgical excision. Cytotoxic agents may also be used such as trichloroacetic acid (TCA), podophyllin or podofilox. Immunomodulatory therapy is also available such as interferon or imiquimod. These treatments are not completely effective in eliminating all viral particles and there is either a high cost incurred or uncomfortable side effects related thereto. In fact, there are currently no commercially available effective antiviral treatments for HPV infection since recurrent warts are common with all current therapies.
The ineffectiveness of the current methods to treat HPV infections has demonstrated the need to identify new means to control or eliminate such infections. In recent years, efforts have been directed towards finding antiviral compounds, and especially compounds capable of interfering with viral replication at the onset of infection.
The life cycle of PV is closely coupled to keratinocyte differentiation. Infection is believed to occur at a site of tissue disruption in the basal epithelium. Unlike normal cells, the cellular DNA replication machinery is maintained as the cell undergoes vertical differentiation. As the infected cells undergo progressive differentiation the viral genome copy number and viral gene expression in turn increase, with the eventual late gene expression and virion assembly in terminally differentiated keratinocytes and the release of viral particles.
The coding strands for each of the papillomaviruses contain approximately ten designated translational open reading frames (ORFs) that have been classified as either early ORFs or late ORFs based on their location in the genome. E1 to E8 are expressed early in the viral replication cycle, and two late genes (L1 and L2) encode the major and minor capsid proteins respectively. The E1 and E2 gene products function in viral DNA replication, whereas E5, E6 and E7 are expressed in connection with host cell proliferation. The L1 and L2 gene products are involved in virion structure. The function of the E3 and E8 gene products is uncertain at present.
Studies of HPV have shown that proteins E1 and E2 are the only two viral proteins that are necessary for viral DNA replication in vitro and in vivo, in addition to the host DNA replication machinery. This requirement is similar to that of bovine papillomavirus type 1 (BPV-1). Indeed, there is a high degree of similarity between E1 and E2 proteins and the ori-sequences of all papillomaviruses (PV) regardless of the viral species and type. Evidence emanating from studies of BPV-1 have shown that E1 possesses ATPase and helicase activities that are required in viral DNA replication.
The E2 protein is a transcriptional activator that binds to E1 protein and forms a complex that binds specifically to the ori sequence (Mohr et al., 1990, Science 250:1694-1699), an interaction that is essential for viral DNA replication. It is believed that E2 enhances binding of E1 to the BPV origin of replication (Seo et al., 1993b, Proc. Natl. Acad. Sci., 90:2865-2869). In HPV, Liu et al. suggested that E2 stabilizes E1 binding to the ori (1995, J. Biol. Chem., 270(45):27283-27291).
To thwart this disease, a chemical entity that would interfere with viral DNA replication is therefore desirable, and the development of new and specific anti-PV, particularly anti-HPV, treatments remains a high priority.
WO 02/50082 published on Jun. 27, 2002 discloses novel indanedione derivatives, pharmaceutical compositions containing such derivatives and methods for using these compounds in the treatment of papilloma virus infection.
WO 01/07027 published on Feb. 1, 2001 to Vertex Pharmaceuticals Incorporated discloses pyrimidine-based inhibitors and analogs thereof for use in inhibiting viral helicases, including viral helicases of flaviviruses, poxviruses and papova viruses.
WO 99/55663 published on Nov. 4, 1999 to Vertex Pharmaceuticals Incorporated discloses substituted aryl compounds and derivatives thereof as inhibitors of inosine-5′-monophosphate dehydrogenase enzyme activity which are useful for mediating IMDH mediated processes, including human papilloma virus replication.
None of the prior art teaches compounds of the present invention as inhibitors of papilloma viral DNA replication.
Structures related to the compounds of the present invention are described in the following patent documents: WO 97/45400, WO 98/47879, and WO 00/24707 of Neurosearch; WO 00/71508; WO 00/71507; WO 00/71509 and WO 00/71493 of Cor Therapeutics; WO 97/49286, WO 00/76501, and WO 00/69435 of SmithKline Beecham; EP 0 974 576 of Mitsui Chemicals; WO 97/24328 and WO 01/02350 of Bayer AG; WO 94/06280 of the University of California; WO 95/11880 of Merck Sharpe & Dohme; and FR 2 763 590 of Synthelabo; U.S. Pat. No. 5,312,924, U.S. Pat. No. 5,216,167; GB 2 124 220 and GB 2 090 834 of Dr. Karl Thomae; U.S. Pat. No. 4,943,315, WO 01/90079 and GB 2 289 893 of BASF AG; JP 09 087237 of Kyowa Hakko Kogya Co.; CA 2,191,757 of Hoechst Schering AgrEvo; EP 0 656 349 and EP 0 588 655 of Ono Pharmaceutical; and EP 0 528 586 of Merck & Co. None of these references teach that such related compounds can be useful in the treatment or prevention of papilloma virus infection.
The present invention therefore provides novel compounds, compositions and methods that inhibit papilloma viral replication. More particularly, the compounds and composition of the present invention interfere with the E1-E2 protein-protein interaction during the viral replication cycle.